Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, China.
Department of Physiology, Navy Medical University, Shanghai, China.
Reproduction. 2021 May 27;162(1):11-20. doi: 10.1530/REP-20-0659.
Urocortins (UCNs), belonging to corticotropin-releasing hormone (CRH) family, exert their function via CRH receptor type 1 (CRHR1) and 2 (CRHR2). Our previous studies have demonstrated that CRH acts on CRHR1 to potentiate prostaglandins (PGs) output induced by inflammatory stimuli in myometrial cells. In the present study, we sought to investigate the effects of UCNs on prostaglandin (PG) output via CRHR2 in cultured human uterine smooth muscle cells (HUSMCs) from pregnant women at term. We found that UCN and UCN 3 treatment promoted PGE2 and PGF2α secretion in a dose-dependent manner. In contrast, UCN2 dose-dependently inhibited PGE2 and PGF2α secretion. Their effects were reversed by CRHR2 antagonist and CRHR2 siRNA. Mechanically, we showed that UCN and UCN3 suppressed cAMP production and led to Gi activation while UCN2 stimulated cAMP production and activated Gs signaling. Further, UCN and UCN3 but not UCN2 activated NF-κB and MAPK signaling pathways through Gi signaling. UCN and UCN3 stimulation of PGs secretion were dependent on Gi/adenylyl cyclase (AC)/cAMP, NF-κB and MAPK signaling pathways. UCN2 suppression of PGs output was through Gs/AC/cAMP signaling pathways. Our data suggest that UCN, UCN2 and UCN3 can finely regulate PGs secretion via CRHR2, which facilitates the functional status of the uterus during pregnancy.
尿皮质素（UCNs）属于促肾上腺皮质激素释放激素（CRH）家族，通过 CRH 受体 1（CRHR1）和 2（CRHR2）发挥作用。我们之前的研究表明，CRH 通过 CRHR1 作用增强了致炎刺激诱导的子宫平滑肌细胞中前列腺素（PGs）的分泌。在本研究中，我们试图研究 UCNs 通过培养的足月妊娠孕妇来源的人子宫平滑肌细胞（HUSMCs）中的 CRHR2 对前列腺素（PG）分泌的影响。我们发现 UCN 和 UCN3 以剂量依赖的方式促进 PGE2 和 PGF2α 的分泌。相反，UCN2 以剂量依赖的方式抑制 PGE2 和 PGF2α 的分泌。其作用可被 CRHR2 拮抗剂和 CRHR2 siRNA 逆转。在机制上，我们发现 UCN 和 UCN3 抑制 cAMP 的产生并导致 Gi 激活，而 UCN2 刺激 cAMP 的产生并激活 Gs 信号。此外，UCN 和 UCN3 通过 Gi 信号激活 NF-κB 和 MAPK 信号通路，但 UCN2 没有。UCN 和 UCN3 对 PGs 分泌的刺激依赖于 Gi/腺苷酸环化酶（AC）/cAMP、NF-κB 和 MAPK 信号通路。UCN2 对 PGs 分泌的抑制作用是通过 Gs/AC/cAMP 信号通路。我们的数据表明，UCN、UCN2 和 UCN3 可以通过 CRHR2 精细调节 PGs 的分泌，这有助于妊娠期间子宫的功能状态。
